Spinal cord injury (SCI) is a devastating event resulting in enormous physical and emotional suffering in patients. SCI patients often live with paralysis and extremely reduced quality of life and productivity. Therapeutic intervention(s) to restore even partial function would significantly increase the quality of life for those patients. Axonal degeneration significantly contributes to functional loss after SCI. Unfortunately, axons in the adult mammalian CNS fail to regenerate after injury due to the non-permissive environment formed primarily by astroglial scars. Astroglial scars not only form a physical barrier, but they also secrete inhibitors, such as chondroitin sulfate proteoglycans (CSPGs), to inhibit the regrowth of injured axons. Previous studies show that degradation of CSPGs, or application of its antagonists, can promote axonal regeneration after SCI. However, these methods only temporarily remove the inhibitory CSPG and are very limited in promoting axonal regeneration and functional recovery after SCI. In this study, we will use novel genetic methods to permanently change the fate of astroglial scars to enhance self-repair of axons after SCI. We hypothesize that in vivo reprogramming of the inhibitory reactive astrocytes into neurons will promote functional recovery after SCI by two synergistic mechanisms: 1) decreasing the astrogliosis and its inhibition to promote regeneration of descending motor tracts; and 2) forming neuronal relay reconnecting the injured descending axons and its caudal target neurons. We will test these hypotheses using three specific aims. Aim 1 will examine in vivo reprogramming of reactive astrocytes after SCI. We hypothesize that forced expression of phenotype specific transcription factors will convert the inhibitory reactive astrocytes into neurons which could integrate into host circuits. Aim 2 will examine whether in vivo astrocyte reprogramming will promote axonal regeneration and functional recovery after SCI. Aim 3 will examine whether combination of in vivo astrocyte reprogramming with multineurotrophin D15A will further promote axonal regeneration and functional recovery after chronic SCI. The proposed studies will help us evaluate the therapeutic potential of in vivo astrocyte reprogramming after SCI and understand the mechanisms of this novel approach for functional recovery. These studies could help us develop the much-needed novel effective therapies for SCI.